title: Molecular mechanisms of hepatocellular apoptosis induced by trovafloxacin-tumor necrosis factor-alpha interaction.
abstract: Idiosyncratic drug-induced liver injury (IDILI) continues to be a significant human health problem. IDILI is characterized as occurring in a minority of individuals exposed to a drug, yet it accounts for as much as 17% of all cases of acute liver failure. Despite these concerns, the mechanisms underlying IDILI remain unknown. Trovafloxacin (TVX), which causes IDILI in humans, also causes hepatocellular death in vitro when combined with tumor necrosis factor-alpha (TNF) treatment. However, the molecular mechanisms involved in this toxicity are not fully characterized. The purpose of this study was to identify mechanisms by which TVX and TNF interact to cause hepatocellular death, with a focus on a human hepatocyte cell line. TVX and TNF interacted to cause cytotoxicity in HepG2 cells at drug concentrations similar to those in people undergoing TVX therapy. TVX/TNF treatment caused apoptosis and DNA damage in HepG2 cells that depended on caspase activation. Prolonged activation of JNK occurred in TVX/TNF-induced cytotoxicity, and treatment with the JNK selective inhibitor SP600125 attenuated cytotoxicity. TVX/TNF cotreatment also caused cytotoxicity in isolated primary murine hepatocytes that was dependent on caspase activation. These results increase understanding of molecular signaling pathways involved in hepatocellular death caused by a drug with idiosyncratic liability in the presence of TNF.
authors.affiliation: * Department of Pharmacology & Toxicology and.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Beggs
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Fullerton
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Miyakawa
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Ganey
authors.forename: Robert A
authors.initials: RA
authors.lastname: Roth
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D024841:Fluoroquinolones / Q000633:toxicity*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000633:toxicity*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C080163:trovafloxacin; D048031:JNK Mitogen-Activated Protein Kinases; D020169:Caspases
keywords: JNK; caspase; hepatotoxicity; idiosyncratic drug-induced liver injury; trovafloxacin.